Design, synthesis and biological evaluation of pyrrolopyrimidine urea derivatives as novel KRASG12C inhibitors for the treatment of cancer

The KRASG12C mutation, which occurs in approximately 14 % of lung adenocarcinomas, has recently become a crucial target for therapy via small molecules that covalently bind to the mutated cysteine. In this study, a novel series of pyrrolopyrimidine derivatives was rationally designed and synthesized, employing a structure-based drug design strategy. Through structure-activity relationship (SAR) analysis, compound SK-17 emerged as a direct and highly potent inhibitor of KRASG12C. Cellular assays illustrated that SK-17 exhibits potent anti- proliferative effects, induces apoptosis, possesses anti-tumor metastasis properties, and effectively inhibits the downstream KRAS pathway in a dose-dependent manner. Moreover, the synergistic enhancement observed when SK-17 is combined with SHP2 inhibitors in vitro underscores its innovative potential in combinatorial therapies. In the xenograft mouse model, SK-17 demonstrated outstanding tumor growth suppression with good safety. Importantly, the in vivo test results show that compound SK-17 has a superior PK profile and lower toxicity in zebrafish test. These results demonstrated the potential of SK-17 with novel scaffold as a promising lead compound targeting KRASG12C to guide in-depth structural optimization.